tbuckley/cabot-search huggingface dataset:
An innate IL-25–ILC2–MDSC axis creates a cancer-permissive microenvironment for <i>Apc</i> mutation–driven intestinal tumorigenesis
Authors: Eric Jou, Noe Rodriguez-Rodriguez, Ana-Carolina F. Ferreira, Helen E. Jolin, Paula A. Clark, Kovilen Sawmynaden, Michelle Ko, Jane E. Murphy, Jonathan Mannion, Christopher Ward, David J. Matthews, Simon J. A. Buczacki, Andrew N. J. McKenzie
Journal: Science Immunology (2022)

Interleukin-25 (IL-25) and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection and are associated with inappropriate allergic reactions. IL-33–activated ILC2s were previously found to augment protective tissue-specific pancreatic cancer immunity. Here, we showed that intestinal IL-25–activated ILC2s created an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression had reduced survival and increased IL-25R–expressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired antitumor responses. Ablation of IL-25 signaling reduced tumors, virtually doubling life expectancy in an Apc mutation–driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promoted intratumoral ILC2s, which sustained tumor-infiltrating MDSCs to suppress antitumor immunity. Therapeutic antibody-mediated blockade of IL-25 signaling decreased intratumoral ILC2s, MDSCs, and adenoma/adenocarcinoma while increasing antitumor adaptive T cell and interferon-γ (IFN-γ)–mediated immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33 as well as ILC2s in cancer cannot be generalized. The protumoral nature of the IL-25–ILC2 axis in CRC highlights this pathway as a potential therapeutic target against CRC.
Human papillomavirus-associated cancers in Taiwan over the last 18 years: The potential impact of screening, vaccination, and smoking.
Authors: Cheng-I Liao, I-Jung Feng, Caitlin Ruth Johnson, Pin-Jie Bin, Chun-Teng Tsai, Daniel Stuart Kapp, John K Chan
Journal: Journal of Clinical Oncology (2022)

10574 Background: Human papillomavirus (HPV) is a causative agent of many human cancers. This study aims to determine the incidences and trends of HPV-associated cancers in the Republic of China. Methods: HPV-associated cancers included: cervical carcinoma, oropharyngeal squamous cell carcinoma (SCC), anal/rectal, vulvo-vaginal, and penile SCC. Deidentified data were obtained from Taiwan’s National Health Insurance Research Database from 2001 to 2018. SEER*Prep 2.6.0, SEER*Stat 8.3.9.2, and Joinpoint regression program 4.9.0.0 were used to calculate incidences and trends of HPV-associated cancers per 100,000. The age-adjusted incidence was adjusted by the WHO 2000 standard population. Results: A total of 55,248 HPV-associated cancers were identified. Of these, 34,730 (62.9%) were identified in women and 20,518 (37.1%) in men. The majority (60.0%) were cervical followed by oropharyngeal at 37.6%, and other HPV-associated cancers comprised 2.4%. Over the 18-year study, the overall age-adjusted incidence of HPV-associated cancers decreased from 13.41 to 8.92 (per/100,000) with an annual decrease of 2.02% ( P&lt; 0.001). More specifically, cervical cancer incidence decreased from 20.42 to 7.70 per 100,000 with an annual decrease of 5.6% ( P&lt; 0.001). Other cancers, such as vaginal and vulvar, decreased 2.34% ( P&lt; 0.001) and 1.82% ( P&lt; 0.001), respectively. With respect to oropharyngeal SCC, the incidence was over 12-fold higher in men compared to women (8.37 vs. 0.67/100,000) with both sexes increasing at 3.61% ( P&lt; 0.001) and 3.59% ( P&lt; 0.001) annually. Anal/rectal SCC increased at 3.55% ( P&lt; 0.001) whereas penile cancer decreased at 2.52% ( P&lt; 0.001). Of note, all HPV-associated cancers among non-smokers decreased 2.02% ( P&lt; 0.001) annually, whereas they increased in smokers at 1.00% ( P&gt; 0.05) per year. This increase in incidence was particularly evident in oropharyngeal SCC and cervical carcinomas. Conclusions: Women comprised over 60% of HPV related cancers, with cervical cancer being most common followed by oropharyngeal cancer. Over the last 18 years, cervical and vulvovaginal cancers decreased, but the rates of oropharyngeal cancers in men was 12-fold higher than women and continues to increase. Public awareness and education of these trends are needed toward prevention and screening.
Dehydrated human amnion-chorion membranes can ameliorate interstitial cystitis in rats by down-regulating inflammatory cytokines and protein coding genes
Authors: C.H. Yang, Y.S. Lin, W.C. Weng, C.H. Lu, C.Y. Hsu, M.C. Tung, C.C. Lin, Y.C. Ou
Journal: European Urology (2022)
Life-cycle health technology assessment for precision oncology.
Authors: Dean A Regier, Deirdre Weymann, Brandon Chan, Cheryl Ho, Howard John Lim, Stephen Yip, Rebekah Rittberg, Sophie Sun, Marco A. Marra, Steven J. M. Jones, Janessa J. Laskin, Samantha Pollard
Journal: Journal of Clinical Oncology (2022)

e18704 Background: Rapid advances in precision oncology challenge timely and sustainable reimbursement decisions. Life-cycle health technology assessment (LC-HTA) can enable conditional patient access to promising precision oncology innovations alongside evidence development. Our objective was to create a life-cycle evaluative framework, called PRecision oncology Evidence Development in Cancer Treatment (PREDiCT). Methods: Through an iterative, health system and stakeholder-informed approach, we designed our LC-HTA framework. Elements supporting data and evidence generation were subsequently implemented within British Columbia, Canada’s provincial cancer control system. Our development, refinement, and pilot implementation process included a structured literature review, multi-disciplinary international expert consultation, a formal gap assessment, and a series of pan-Canadian inter-disciplinary stakeholder workshops to refine framework elements. Results: We engaged n = 15 pan-Canadian and international stakeholders to co-develop the LC-HTA framework. Defining framework components include: (a) managed access that defines the time horizon and pricing conditions of real-world healthcare system trialing; (b) collection of core data elements required to enable economic evaluation of precision oncology using real world data; (c) externally leveraged real world data and evidence generation to determine comparative effectiveness, cost-effectiveness, and the value of conducting additional research; and (d) data interpretation updating decisions, including investment, continued evaluation, or disinvestment from managed access. Key to the success of early framework implementation is the expansion of infrastructure to enable routine collection and linkage of genomic sequencing and cancer treatment data, patient quality of life and clinical outcomes, as well as health resource use spanning the diagnostic, treatment, and follow up trajectory. Conclusions: Sustainable integration of precision oncology requires the design and implementation of learning healthcare systems (LHS) that integrate genomic data with other health information. LC-HTA moves beyond static estimates of clinical and cost-effectiveness to continuously generate evidence that reduces evidentiary uncertainty and supports life-cycle decisions. We are embarking on a PREDiCT pilot to implement the framework in real-time to demonstrate the ability of real-world data to support life cycle evaluation.
Urinary continence outcome of patients with epithelialized cavity formation after excessive vesicourethral anastomotic leak post radical prostatectomy
Authors: D.K. Filipas, M. Graefen, M. Fisch, R.J. Schulz, M. Kachanov, P. Tennstedt, L. Hahn, J.L. Hohenhorst, R.M. Pose
Journal: European Urology (2022)
Disparity in initiation of checkpoint inhibitors among metastatic melanoma and lung cancer.
Authors: Meng Li, Kai-Ping Eric Liao, Alice Chen, Mackenzie Wehner, Ya-Chen Tina Shih
Journal: Journal of Clinical Oncology (2022)

1583 Background: Checkpoint inhibitors are transforming cancer care. However, the high prices of these medicines raise concerns over their affordability and disparity in use. The objective of this study is to describe the disparity in initiating checkpoint inhibitors and examine patient- and area-level factors associated with delayed initiation. Methods: This study is a retrospective cohort study using Optum data. We identified commercially insured patients newly diagnosed with metastatic lung cancer and melanoma since the introduction of checkpoint inhibitors in these cancers (lung cancer cohort: diagnosed between January 2015 and December 2020; melanoma cohort: diagnosed between January 2011 and December 2020). Time from metastatic cancer diagnosis to initiating checkpoint inhibitors was analyzed using Cox proportional hazard models. Independent variables included county-level measures (percentage of black population, percentage of Hispanic population, percentage of other minority, percentage of population living below poverty line, rurality, number of medical oncologist per population, and having a National Cancer Institute designated cancer center) and patient-level characteristics (age, sex, Charlson comorbidity index, any dual eligibility, Medicare Advantage, and year of diagnosis). We clustered standard errors at the county level. Results: The percentage of metastatic lung cancer and metastatic melanoma patients on checkpoint inhibitors increased from 23% to 52% from 2015 to 2020 and from 22% to 58% from 2011 to 2020. Counties with greater percentage of black, Hispanics, and other minorities were high urban with greater density of medical oncologists and NCI-designated cancer centers. However, greater percentage of Hispanic population in a county was associated with significantly slower initiation of checkpoint inhibitors for both the lung cancer and the melanoma cohorts (hazard ratios [HR]: 0.937 and 0.946, respectively; p-values: &lt; 0.001 and 0.014, respectively). Percentage of other minority population in a county was associated with slower initiation for metastatic lung cancer (HR: 0.983; p-value: &lt; 0.001). No other county-level factors had a significant coefficient from the multivariate Cox models. In terms of patient-level characteristics, older age, female, more comorbidities, any dual eligibility, and Medicare Advantage were associated with significantly slower initiation for the lung cancer cohort and older age and female were associated with significantly slower initiation for the melanoma cohort. Conclusions: Commercially insured metastatic lung cancer and melanoma patients who lived in counties with greater percentage of Hispanic population had slower initiation of checkpoint inhibitors after their cancer diagnosis, despite the fact that those counties had greater density of medical oncologists and NCI-designated cancer centers.
ALK fusion typing and response to crizotinib in ALK+ lung cancer-naive patients.
Authors: Xinliang Zhou, Liyuan He, Zhisong Fan, Jing Zuo, Li Feng, Long Wang, Jing Han, Jiayin Liu, Xue Zhang, Dan Li, Feiran Liu, Honghui Zhao, Yudong Wang
Journal: Journal of Clinical Oncology (2022)

e21008 Background: Anaplastic lymphoma kinase (ALK) is one of the major oncogenic driver genes in lung cancer, and fusion as the main mutation type, of which EML4 is the most common fusion ligand. With the development of next-generation sequencing (NGS), some other rare fusion ligands and complex fusions have been discovered. The prognosis of patients with EML4-ALK fusion, non EML4-ALK fusion and multiple ALK fusion was different. Methods: We retrospectively analyzed NGS (including tissue, blood, or other body fluid samples) in 61 patients with ALK[+] lung cancer, including 59 patients with NSCLC and 2 patients with SCLC. Grouping was determined according to whether it was EML4-ALK fusion and multiple fusion. Results: In our data, the partner fused to the ALK gene are diverse, including EML4, KIF5B, TSN and others. Among them, EML4 was the most common ligand in ALK[+] NSCLC, accounting for 93.2% (55/59). Among the different fusion sites of EML4-ALK, V1 (E13:A20) and V3 (E6:A20) mutations were the most common, accounting for 45.5% (25/55) and 41.8% (23/55), respectively. Several novel ALK fusion partners were discovered in this study, including MCFD2, LINC01251, MVP17, CREG2, LINCO1498 and so on. In addition, the incidence of intergenic sequence-ALK fusions was 16.4% (10/61), such as ANXA4-ALK(A[intergenic]:A20), CREG2-ALK (C[intergenic]:A20), HCN1-ALK(H[intergenic]:A20), TSN-ALK(T[intergenic]:A20), RSAD2-ALK(R [intergenic]:A20) and so on. 19.0% (12/61) of the patient had multiple fusion, of which only one patient had multiple fusion of EML4-ALK (V2+V5'+V3a/b), and the remaining patients had co-fusion of EML4-ALK and non EML4-ALK (Table). V3 were more likely to coexist with non EML4-ALK fusions than V1 or other variants (P = 0.047). Multiple fusions were more likely to occur with non EML4-ALK fusions (P &lt; 0.000). Compared with EML4-ALK fusion, mPFS treated with crizotinib in non EML4-ALK fusion were significantly shorter (18.2 vs. 8.5 months, P = 0.035). In the context of crizotinib treatment, multiple fusions were associated with worse mPFS compared with single fusions (13.8 vs. 8.4 months, P = 0.008). In addition, For SCLC patients with ALK fusion (n = 2), the PFS of crizotinib treatment were 8.0 and 30.6 months, respectively. Conclusions: Due to the heterogeneity of tumor development resulting in the diversity of ALK fusions, non EML4-ALK fusions and multiple fusions imply a poorer response to crizotinib. ALK gene status prior to ALK-TKI therapy helps predict drug efficacy and patient prognosis.[Table: see text]
Price variability of pembrolizumab in New York City from 2016-2021.
Authors: Syed Hussaini, Jordan Johnson, Fumiko Chino
Journal: Journal of Clinical Oncology (2022)

6601 Background: There is poor compliance among cancer centers with price transparency rules set forth by the CMS in 2021. Service charges higher than what a hospital reasonably expects to be reimbursed may both prevent competitive price shopping by the consumer and result in catastrophic financial toxicity for small payors and under/uninsured individuals. We investigated variability in the charged and reimbursed payments for pembrolizumab infusion within one metro area utilizing Medicare claims. Methods: Medicare claims data from 2016 through 2021 for all pembrolizumab (HCPCS J9271) infusions in a hospital outpatient department were selected from the Definitive Healthcare claims database for medical oncology providers in New York City (NYC). Average charges, reimbursements, and total claims were obtained for the 6 largest prescribers by volume. Annual percentage changes (APC) were calculated to evaluate trends during study period. Prices are presented as inflation adjusted numbers (charged and reimbursed; 2021 dollars). Analyses were performed in Excel (Microsoft Corp). Results: Our analysis included 5 NCI-designated cancer centers (NCI-A, NCI-B, NCI-C, NCI-D) of which 1 was PPS (Prospective Payment System)-exempt (NCI-PPS). One hospital was non-NCI and 4 hospitals were part of the discounted 340B Drug Pricing Program (NCI-A, NCI-B, NCI-D, Non-NCI). From 2016 to 2021, total Medicare claims increased 793 to 1537, and total payments to all centers increased from $5.4M to $16.3M. NCI-PPS comprised 61% of claims, and 65% of total payments in 2021. Average charge for pembrolizumab in 2021 ranged from $20,130 (NCI-PPS) to $155,825 (NCI-D/340B). During study period, APC ranged from +1.7% (NCI-A/340B) to +25.4% (NCI-D/340B). Despite wide variability in charged amounts for Medicare claims, re-imbursed amounts were similar across centers (range: $6227-9623, 2021). Conclusions: There is significant variability in charges for pembrolizumab in Medicare claims with price increases outpacing the annual rate of inflation. Within NYC, the highest charges were from a 340B hospital; NCI-PPS had higher volume and total payments but consistently lower charged prices each year. Our study highlights extreme price variability, and has policy implications for price transparency requirements and uniform rate setting to establish payment levels and control rate of annual growth. [Table: see text]
ETMR-01. Management of CNS tumor with BCOR internal tandem duplication with multimodalities therapy: Surgery, Intensive Chemotherapy, and Radiation
Authors: Nahla Ali Mobark, Musa Alharbi, Walid Ballourah, Abdulrahman Alsultan, Fahad El Manjomi, Zaid AlNaqib, Ayman Al-Banyan, Ali Abdullah O Balbaid, Malak Abedalthagafi, MD
Journal: Neuro-Oncology (2022)

Abstract The 2021WHO CNS tumor classification includes CNS tumors with internal tandem duplications in the BCL6 corepressor (BCOR) gene as a new entity of CNS embryonal tumors labelled high-grade neuroepithelial tumors with BCOR alterations (HGNET-BCOR) are characterized by genetic aberrations in the BCOR gene located at Xp11.4, leading to increased expression of BCOR mRNA and distinct DNA methylation profiles. currently no agreement on the optimal strategy to manage these rare tumors, which mostly occur in young children These tumors are usually treated as high grade glioma HGG with upfront radiation therapy with poor outcome. We report 2.5 years old boy presenting with headache and vomiting. MRI showed a well-defined left cerebellar mass, hyperintense in T2 and hypointense in T1, with restricted diffusion and no spinal CSF seeding metastases. He underwent gross surgical resection of the tumor initial pathological diagnosis was epithelioid high grade malignant neoplasm. Brain tumor methylation classifier analysis of resected tumor tissue confirmed a CNS tumor with BCOR internal tandem duplication (WHO grade 4). The patient was treated per COG ACNS0334 (3 induction cycles of vincristine, cyclophosphamide, cisplatin, etoposide, HDMTX, followed by consolidation with 3 cycles of carboplatin and thiotepa with autologous hematopoietic stem cell rescue). MRI brain before the start of chemotherapy showed a small recurrent mass within the surgical cavity. post-induction MRI detected stable-sized residual lesion in the surgical cavity; however, post-consolidation MRI showed complete resolution of the residual mass. The patient subsequently received craniospinal irradiation (36 Gy [CSI]) with a boost to the tumor bed up to 54 GY. By the time of writing this report our patient is still in complete remission. Our case showed that this aggressive brain tumor may respond well to intensive multimodalities therapy Further case studies and international prospective trials are needed to optimize the clinical management of these rare tumors.
Do national policies for complaint handling in English hospitals support quality improvement? Lessons from a case study
Authors: J van Dael, TW Reader, AT Gillespie, L Freise, A Darzi, EK Mayer
Journal: Journal of the Royal Society of Medicine (2022)

Objectives A range of public inquiries in the English National Health Service have indicated repeating failings in complaint handling, and patients are often left dissatisfied. The complex, bureaucratic nature of complaints systems is often cited as an obstacle to meaningful investigation and learning, but a detailed examination of how such bureaucratic rules, regulations, and infrastructure shape complaint handling, and where change is most needed, remains relatively unexplored. We sought to examine how national policies structure local practices of complaint handling, how they are understood by those responsible for enacting them, and if there are any discrepancies between policies-as-intended and their reality in local practice. Design Case study involving staff interviews and documentary analysis. Setting A large acute and multi-site NHS Trust in England. Participants Clinical, managerial, complaints, and patient advocacy staff involved in complaint handling at the participating NHS Trust ( n=20). Main outcome measures Not applicable. Results Findings illustrate four areas of practice where national policies and regulations can have adverse consequences within local practices, and partly function to undermine an improvement-focused approach to complaints. These include muddled routes for raising formal complaints, investigative procedures structured to scrutinize the ‘validity’ of complaints, futile data collection systems, and adverse incentives and workarounds resulting from bureaucratic performance targets. Conclusion This study demonstrates how national policies and regulations for complaint handling can impede, rather than promote, quality improvement in local settings. Accordingly, we propose a number of necessary reforms, including patient involvement in complaints investigations, the establishment of independent investigation bodies, and more meaningful data analysis strategies to uncover and address systemic causes behind recurring complaints.
Treatment outcomes for newly diagnosed, untreated <i>TP53</i>-mutated acute myeloid leukemia: A systematic review and meta-analysis.
Authors: Naval Guastad Daver, Shahed Iqbal, Camille Renard, Rebecca J. Chan, Ken Hasegawa, Hao Hu, Preston Tse, Jiajun Yan, Michael J. Zoratti, Feng Xie, Giridharan Ramsingh
Journal: Journal of Clinical Oncology (2022)

e19020 Background: TP53 mutations are present in 10%–15% of patients with acute myeloid leukemia (AML) and are associated with resistance to therapy and poor outcomes. Currently available frontline therapies for TP53-mutated ( TP53m) AML include intensive chemotherapy (IC), hypomethylating agents (HMA), and venetoclax combined with HMA (VEN+HMA). This systematic review and meta-analysis evaluated outcomes associated with IC, HMA, and VEN+HMA in newly diagnosed, untreated TP53m AML. Methods: EMBASE and MEDLINE were searched May 20, 2021 to identify studies of interest. Single-arm data on complete remission (CR), CR with incomplete hematologic recovery (CRi), median overall survival (mOS), event-free survival (EFS), and duration of response (DoR) were extracted and pooled for each treatment. Response rates were pooled using random-effects models; the median of medians method was used for time-related outcomes. Results: Of 3006 abstracts identified, 17 publications describing 12 studies met the inclusion criteria: 6 were randomized clinical trials (RCTs), 2 were single-arm trials, and 4 were retrospective studies. Outcomes are displayed in the Table. CR rate was highest with IC at 43% (95% CI, 30%, 56%), followed by VEN+HMA, 33% (22%, 47%), and HMA alone 21% (7%, 49%). Rates of CR/CRi were 49% (37%, 60%) for VEN+HMA, 46% (39%, 53%) for IC, and 13% (2%, 48%) for HMA alone. mOS was similarly low across the 3 treatments: IC, 6.5 months (N=155; 5.1, 8.5); VEN+HMA, 6.2 (N=73; 5.2, 7.2); HMA, 6.1 (N=34; 4.9, 7.2). Conclusions: CR, CR/CRi, and mOS were low across all treatments for patients with newly diagnosed, untreated TP53m AML. Addition of venetoclax to HMA showed a trend toward improved response vs HMA alone but not for mOS. There is a significant unmet need for more effective treatment for this very difficult-to-treat population. [Table: see text]
Case 17-2022: A 17-Year-Old Boy with Chest Pain
Authors: Puneeta Arya, Sjirk J. Westra, Oscar J. Benavidez, Marc D. Natter, Mandakolathur R. Murali
Journal: New England Journal of Medicine (2022)

A 17-year-old boy was admitted to the pediatric ICU with chest pain, syncope, electrocardiographic abnormalities, and elevated creatine kinase and troponin T. He had been well until 5 days earlier, when fever, nausea, diarrhea, muscle aches, and chest pain developed.